The scarcity of precious metals has led to the development of sustainable strategies for metal-catalyzed cross-coupling reactions. The establishment of new catalytic methods using iron is attractive owing to the low cost, abundance, ready availability, and very low toxicity of iron. In the last few years, sustainable methods for iron-catalyzed cross-couplings have entered the critical area of pharmaceutical research. Most notably, iron is one of the very few metals that have been successfully field-tested as highly effective base-metal catalysts in practical, kilogram-scale industrial cross-couplings. In this Minireview, we critically discuss the strategic benefits of using iron catalysts as green and sustainable alternatives to precious metals in cross-coupling applications for the synthesis of pharmaceuticals. The Minireview provides an essential introduction to the fundamental aspects of practical iron catalysis, highlights areas for improvement, and identifies new fields to be explored.

We report that cyclic ureas (DMI, DMPU) are efficient and sustainable alternatives to reprotoxic NMP in challenging iron-catalyzed C(sp2)–C(sp3) alkylations of aryl chlorides and tosylates with alkyl Grignard reagents.

Oxygen-based electrophiles have emerged as some of the most valuable cross-coupling partners in organic synthesis due to several major strategic and environmental benefits, such as abundance and potential to avoid toxic halide waste. In this context, iron-catalyzed C-O activation/cross-coupling holds particular promise to achieve sustainable catalytic protocols due to its natural abundance, inherent low toxicity, and excellent economic and ecological profile. Recently, tremendous progress has been achieved in the development of new methods for functional-group-tolerant iron-catalyzed cross-coupling reactions by selective C-O cleavage. These methods establish highly attractive alternatives to traditional cross-coupling reactions by using halides as electrophilic partners. In particular, new easily accessible oxygen-based electrophiles have emerged as substrates in iron-catalyzed cross-coupling reactions, which significantly broaden the scope of this catalysis platform. New mechanistic manifolds involving iron catalysis have been established; thus opening up vistas for the development of a wide range of unprecedented reactions. The synthetic potential of this sustainable mode of reactivity has been highlighted by the development of new strategies in the construction of complex motifs, including in target synthesis. The most recent advances in sustainable iron-catalyzed cross-coupling of C-O-based electrophiles are reviewed, with a focus on both mechanistic aspects and synthetic utility. It should be noted that this catalytic manifold provides access to motifs that are often not easily available by other methods, such as the assembly of stereodefined dienes or C(sp )-C(sp ) cross-couplings, thus emphasizing the synthetic importance of this mode of reactivity.

Iron-catalyzed cross-coupling reactions allow sustainable formation of C-C bonds using cost-effective, earth-abundant base-metal catalysis for complex syntheses of pharmaceuticals, natural products, and fine chemicals. The major challenge to maintain full sustainability of the process is the identification of green and renewable solvents that can be harnessed to replace the conventional solvents for this highly attractive reaction. Herein, iron-catalyzed cross-coupling of aryl chlorides and tosylates with challenging organometallic reagents possessing β-hydrogens is found to proceed in good to excellent yields with the green, sustainable, and eco-friendly 2-methyltetrahydrofuran (2-MeTHF) as solvent. The reaction operates with excellent functional group tolerance under very mild conditions. Furthermore, large-scale cross-coupling, cross-coupling of heteroaromatic substrates, and cross-coupling of challenging aryl tosylates and carbamates mediated by Fe-N-heterocyclic carbene catalytic systems in eco-friendly 2-MeTHF were also carried out. The developed method was applied to the key cross-coupling in the synthesis of a fibrinolysis inhibitor, further highlighting the potential of 2-MeTHF as a general solvent for sustainable iron-catalyzed cross-coupling reactions.

Alkylated benzosulfonamides are compounds of high importance in organic synthesis, including the production of pharmaceuticals, agrochemicals, and plasticizers. We report the iron-catalyzed C­(sp2)–​C­(sp3) cross-coupling of chlorobenzosulfonamides with alkyl Grignard reagents under mild and sustainable conditions. Electronically and sterically varied benzosulfonamides as well as challenging alkyl organometallics containing β-hydrogen afford alkylated benzosulfonamides in high to excellent yields. Sulfonamide represents the most reactive activating group for iron-catalyzed cross-coupling. The process affords alkylated benzenesulfonamides poised for medicinal chemistry applications and traceless reductive cleavage.

Planarity of the amide bond represents one of the most widely recognized properties of amides. Herein, we report a combined structural and computational study on the effect of ortho-substitution on resonance and barriers to rotation in tertiary aromatic amides. We demonstrate that ortho-chloro substitution in a class of benzamides that are important from the reactivity and medicinal chemistry perspective results in increased barriers to rotation around both the N-C(O) and C-C(O) axes. The effect of steric hindrance on structures, resonance energies, barriers to rotation, and proton affinities is discussed. The present study strongly supports the use of ortho-substitution in common benzamides to strengthen amidic resonance.

We report the Pd-catalyzed Suzuki−Miyaura cross-coupling of aliphatic amides. Although tremendous advances have been made in the cross-coupling of aromatic amides, C−C bond formation from aliphatic amides by selective N−C(O) cleavage has remained a major challenge. This longstanding problem in Pd catalysis has been addressed herein by a combination of (1) the discovery of N,N-pym/Boc amides as a class of readily accessible amide-based reagents for cross-coupling and (2) steric tuning of well-defined Pd(II)-NHC catalysts for cross-coupling. The methodology is effective for the cross-coupling of an array of 3°, 2°, and 1°aliphatic amide derivatives. The catalyst system is user-friendly, since the catalysts are readily available and are air-and benchstable. Mechanistic studies strongly support an amide bond twist and external n N → π* CO/Ar delocalization as a unified enabling feature of N,N-pym/Boc amides in selective N−C(O) bond activation. The method provides a rare example of Pd-NHC-catalyzed cross-coupling of aliphatic acyl amide electrophiles.

A series of group 4 metal complexes bearing amine-bis(phenolate) ligands with the amino side-arm donor: (l-O)2 (2d) are used in ethylene and propylene homopolymerization, and ethylene/1-octene copolymerization. All complexes, upon their activation with Al(iBu) 3 /Ph 3 CB(C 6 F 5 ) 4 , exhibit reasonable catalytic activity for ethylene homo-and copolymerization giving linear polyethylene with high to ultra-high molecular weight (600Á3 10 3 -3600Á3 10 3 g/mol). The activity of 1a/Al(iBu) 3 /Ph 3 CB(C 6 F 5 ) 4 shows a positive comonomer effect, leading to over 400% increase of the polymer yield, while the addition of 1-octene causes a slight reduction of the activity of the complexes 2a-2d.The complexes with the NMe 2 donor group (2a, 2d, 1a) display a high ability to incorporate a comonomer (up to 9-22 mol%), and the use of a bulkier donor group, N(iPr) 2 (2b, 2c), results in a lower 1-octene incorporation. All the produced copolymers reveal a broad chemical composition distribution. In addition, the investigated complexes polymerized propylene with the moderate (1a, 2a) to low (2b-2d) activity, giving polymers with different microstructures, from purely atactic to isotactically enriched (mmmm 5 28%).